Metal phosphates (for example, alkaline earth phosphates such as magnesium phosphate and calcium phosphate) have numerous applications. Alkaline earth phosphates are used in anti-rust coatings, in flame retardants, in antacids, and in producing fluorescent particles. Iron phosphates find application in cathode material for lithium ion batteries. Aluminum, manganese, cobalt, tin, and nickel phosphates are used in heterogeneous catalysis. Zinc phosphate is commonly used as a pigment in anti-corrosion protection. Zirconium phosphates are used as solid acid catalysts. Various lanthanide phosphates are useful as fluorescent and laser materials.
Calcium phosphates are particularly useful, however, due to their classification as biocompatible materials. Under physiological conditions calcium phosphates can dissolve, and the resulting dissolution products can be readily assimilated by the human body. Biocompatible calcium phosphates include hydroxyapatite (HAP; [Ca5(PO4)3OH]), dicalcium phosphate (DCP; [Ca(HPO4).2H2O]), tricalcium phosphate (TCP; [Ca3(PO4)2]), tetracalcium phosphate (TTCP, [Ca4O(PO4)2]), and amorphous calcium phosphate.
Of the biocompatible calcium phosphates, hydroxyapatite can be more stable under physiological conditions. Thus, hydroxyapatite has been used for bone repair after major trauma or surgery (for example, in coatings for titanium and titanium alloys). Hydroxyapatite has also been used in the separation and purification of proteins and in drug delivery systems. Other calcium phosphates have been used as dietary supplements in breakfast cereals, as tableting agents in some pharmaceutical preparations, in feed for poultry, as anti-caking agents in powdered spices, as raw materials for the production of phosphoric acid and fertilizers, in porcelain and dental powders, as antacids, and as calcium supplements.
For some of these applications (for example, adjuvants for vaccines, cores or carriers for biologically active molecules, controlled release matrices, coating implant materials, protein purification, and dental applications), non-agglomerated nanoparticles of calcium phosphate can be desired. The preferred sizes, morphologies, and/or degrees of crystallinity of the nanoparticles vary according to the nature of each specific application.
Numerous methods have been used for the synthesis of hydroxyapatite nanoparticles including chemical precipitation, hydrothermal reactions, freeze drying, sol-gel formation, phase transformation, mechanochemical synthesis, spray drying, microwave sintering, plasma synthesis, and the like. Hydroxyapatite nanoparticles have often been synthesized by the reaction of aqueous solutions of calcium ion-containing and phosphate ion-containing salts (the so-called “wet process”), followed by thermal treatment. Nanoparticles obtained by this method generally have had a needle-like (acicular) morphology with varying degrees of crystallinity, depending upon the nature of the thermal treatment. Such acicular nanoparticles can be used as coating implant materials but have limited or no use in some of the other applications mentioned above.
Various additives have been used to control hydroxyapatite particle growth and/or to alter hydroxyapatite particle morphology but with only limited success. For example, polymers and solvent combinations have been used in the above-described wet process to suppress crystal growth along one axis, but only a few approaches have provided particles with decreased aspect ratios or particles of spherical morphology but relatively large particle size.
Solid-state reaction of precursors, plasma spraying, pulsed laser deposition, and flame spray pyrolysis methods have resulted in hydroxyapatite nanoparticles of different morphologies (for example, spherical or oblong), but these have often been in the form of micron-sized agglomerates of nanoparticles that have been of limited use in certain applications. Numerous researchers have carried out post-synthesis surface modification of hydroxyapatite to de-agglomerate the particles.
Surfactant-based systems have also been widely used in the synthesis of hydroxyapatite nanoparticles. For example, hydroxyapatite nanoparticles have been prepared by an emulsion process in which reverse micelles are produced in an oil phase by using a surface-active agent, followed by the reaction of phosphate and calcium ions in a water phase in the micelles. Disadvantages of such “water in oil” reverse microemulsion processes include the use of relatively large amounts of oil and surfactant (resulting in the need for recycling these materials or, alternatively, accepting a relatively low production yield) and the need for appropriate disposal of nonbiodegradable surfactants.
Generally the synthesis of spherical hydroxyapatite nanoparticles has involved the use of either surfactants or polymers to control the morphology and the size of the resulting particles. The capability of such methods to provide nanoparticles in the form of redispersible dry powder (for example, dry powder that can be redispersed in an appropriate solvent to provide a non-agglomerated nanoparticle dispersion), however, has generally not been evident.
Thus, current processes for the preparation of nanosized calcium phosphate particles can utilize expensive starting materials (for example, calcium alkoxide), can require the use of surfactants, can be complex, can provide agglomerates, can provide slow particle growth, can provide insufficient control over particle size and/or particle morphology, can fail to provide often preferred particle sizes (for example, average primary particle diameters of about 1 to about 50 nm), and/or can fail to provide nanoparticles that are redispersible.